日前，荷蘭研究人員在線發(fā)表了題為《RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis in Zebrafish Embryos by Targeting Smad7 for Degradation》研究論文,，發(fā)現(xiàn)了控制胚胎干細(xì)胞命運(yùn)和形態(tài)發(fā)生的機(jī)制,，并證明RNF12在TNF-β家族信號轉(zhuǎn)導(dǎo)中起到?jīng)Q定性作用。該研究論文發(fā)表在Molecular Cell上,。
Smad7蛋白是一個調(diào)節(jié)TNF-β家族/Smad7反應(yīng)的拮抗劑,，但其調(diào)節(jié)機(jī)制還不明白。
首先,，我們確定編碼RING結(jié)構(gòu)域的E3連接酶RNF12為TNF-β信號通路中的決定性組成成分,。RNF12的消耗顯著地降低TNF-β家族/Smad7誘導(dǎo)的效應(yīng)，相反,，RNF12的異常表達(dá)強(qiáng)烈地增強(qiáng)TNF-β家族/Smad7誘導(dǎo)的效應(yīng),。
其次，在斑馬魚胚胎早期,，Nodal依賴和BMP依賴的信號轉(zhuǎn)導(dǎo)和形態(tài)發(fā)生事件時,，RNF12與Smad7是對抗的。由Smad7消耗或異常引起的原腸胚形成缺陷可以通過RNF12功能的獲得或缺失而恢復(fù),。
研究發(fā)現(xiàn)造成以上事件的機(jī)制是RNF12特異地與Smad7結(jié)合并引起其多泛素化而降解,。這些發(fā)現(xiàn)證明RNF12在TNF-β家族信號轉(zhuǎn)導(dǎo)中起到?jīng)Q定性作用。（生物谷 Bioon.com)
doi.org/10.1016/j.molcel.2012.04.003
PMC:
PMID:
RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis in Zebrafish Embryos by Targeting Smad7 for Degradation
Long Zhang,， Huizhe Huang,， FangFang Zhou， Joost Schimmel,， Cristina Gontan Pardo,， Tingting Zhang， Tahsin Stefan Barakat,， Kelly-Ann Sheppard,， Craig Mickanin， Jeff A. Porter,， Alfred C.O. Vertegaal,， Hans van Dam1， Joost Gribnau,， Chris X. Lu,， Peter ten Dijke，
1 Department of Molecular Cell Biology and Centre for Biomedical Genetics,， Leiden University Medical Center,， Postbus 9600 2300 RC Leiden， The Netherlands
2 Faculty of Basic Medical Sciences， Chonqing Medical University,， Medical College Road 1,， 400016 Chongqing， China
3 Department of Reproduction and Development,， Erasmus MC,， University Medical Center， PO Box 2040,， 3000 CA Rotterdam,， The Netherlands
4 Novartis Institutes for Biomedical Research， 250 Massachusetts Avenue,， Cambridge,， MA 02139， USA
Summary
TGF-β members are of key importance during embryogenesis and tissue homeostasis. Smad7 is a potent antagonist of TGF-β family/Smad-mediated responses,， but the regulation of Smad7 activity is not well understood. We identified the RING domain-containing E3 ligase RNF12 as a critical component of TGF-β signaling. Depletion of RNF12 dramatically reduced TGF-β/Smad-induced effects in mammalian cells,， whereas ectopic expression of RNF12 strongly enhanced these responses. RNF12 specifically binds to Smad7 and induces its polyubiquitination and degradation. Smad7 levels were increased in RNF12-deficient mouse embryonic stem cells， resulting in mitigation of both BMP-mediated repression of neural induction and activin-induced anterior mesoderm formation. RNF12 also antagonized Smad7 during Nodal-dependent and BMP-dependent signaling and morphogenic events in early zebrafish embryos. The gastrulation defects induced by ectopic and depleted Smad7 were rescued in part by RNF12 gain and loss of function,， respectively. These findings demonstrate that RNF12 plays a critical role in TGF-β family signaling.
